Hematopoietic stem cells (HSCs) are required for lifelong blood cell production and, to prevent exhaustion, the majority of HSCs are deeply quiescent during steady-state hematopoiesis. Paracrine factors produced by specialized bone marrow niche cells maintain HSC quiescence. During times of hematologic stress, HSCs are rapidly recruited into cell cycle and undergo extensive self-renewal and differentiation to meet increased hematopoietic demands. A great deal is known about how HSCs are mobilized during these periods of stress. Proteolytic enzymes such as MMP-9, cathepsin G and elastase cleave the chemokines (e.g., CXCL12), cytokines (e.g., KITL) and adhesive interactions that retain HSCs in the niche and maintain their quiescence. Circulating cytokine levels increase in response to cytopenias, tissue injury and inflammation and this reinforces HSPC proliferation. Yet it is not known how these processes wind down to allow HSCs to withdraw from cell cycling and return to quiescence. TGFβ has also been shown to block cytokine-driven HSC cycling (Batard et al., J Cell Sci 113:383-390 (2000); Scandura et al., Proc Natl Acad Sci USA 101:15231-15236 (2004); Yamazaki et al., Blood 113:1250-1256 (2009)).
TGFβ is one of the most potent inhibitors of cytokine-driven HSC proliferation in vitro (Batard et al., J Cell Sci 113:383-390 (2000); Blank et al., Leukemia 25:1379-1388 (2011); Fortunel et al., Hematol J 1:126-135 (2000); Fortunel et al., Blood 96:2022-2036 (2000); Scandura et al., Proc Natl Acad Sci USA 101:15231-15236 (2004); Sitnicka et al., Blood 88:82-88 (1996)), but its role in hematopoiesis has been harder to establish (Capron et al., Blood 116:1244-1253 (2010); Dickson et al., Development 121:1845-1854 (1995); Larsson et al., Blood 102:3129-3135 (2003); Larsson et al., Exp Hematol 33:592-596 (2005); Larsson et al., Embo J 20:1663-1673 (2001); Oshima et al., Dev Biol 179:297-302 (1996)). Identifying HSC defects in knockouts of TGFβ, or of its receptors Tgfbr1 (Alk5) and Tgfbr2, was difficult because the engineered mice develop a transplantable, lethal inflammatory disorder that largely prevents analysis of steady-state hematopoiesis in adult mice (Gorelik et al., Immunity 12:171-181 (2000); Letterio et al., J Clin Invest 98:2109-2119 (1996); Leveen et al., Blood 100:560-568 (2002); Yaswen et al., Blood 87:1439-1445 (1996)). Nonetheless, recent studies using a variety of elegant approaches to circumvent this lethal inflammatory disorder strongly suggest that TGFβ, signaling through Tgfbr2 and recruiting Smad4, is a putative niche factor that can maintain HSC quiescence during steady-state hematopoiesis (Blank et al., Blood 108:4246-4254 (2006); Karlsson et al., J Exp Med 204:467-474 (2007); Yamazaki et al., Cell 147:1146-1158 (2011); Yamazaki et al., Blood 113:1250-1256 (2009); Yamazaki et al., Embo J 25:3515-3523 (2006)).